Evaluation of urinary biomarkers for radical-induced liver damage in rats treated with carbon tetrachloride.
Carbon tetrachloride (CCl4) is a model compound for inducing free radical damage in liver. In this study 10 biomarkers in rats treated i.p. with three different single doses of CCl4 (0.25, 0.50, and 1.00 ml/kg body wt) were measured dose and time dependently and compared to evaluate these urinary products as noninvasive biomarkers for radical damage. Eight degradation products of lipid peroxides, namely, formaldehyde, acetaldehyde, acetone, propanal, butanal, pentanal, hexanal, and malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and coproporphyrin III were measured in this study. As general measures of toxicity, several clinical chemical parameters (n = 12) and histopathological damage were determined. A dose-dependent increase in both the clinical parameters and the lipid degradation products was found. Increases in lipid degradation products were statistically significant at doses of 0.5 and 1 ml/kg CCl4. An increase in these products was already found in the first 12 h after exposure. At the lowest dose, 0.25 ml/kg CCl4, acetaldehyde and propanal already showed a statistically significant increase as well. No change in the urinary levels of 8-OH-dG could be found in this study and a decrease in the urinary excretion of coproporphyrin III was found. It is concluded that 8-OH-dG and coproporphyrin III are not useful biomarkers for radical damage induced by CCl4. Lipid degradation products, however, are promising noninvasive biomarkers for in vivo radical damage, although the precise specificity of these biomarkers for damage induced by radicals needs to be further investigated.
de Zwart
L L
LL
Leiden-Amsterdam Center for Drug Research (LACDR), Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Hermanns
R C
RC
Meerman
J H
JH
Commandeur
J N
JN
Salemink
P J
PJ
Vermeulen
N P
NP
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000096:Acetone / Q000652:urine; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000447:Aldehydes / Q000652:urine; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000652:urine*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D003306:Coproporphyrins / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000633:toxicity; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D015415:Biomarkers; D003306:Coproporphyrins; D005609:Free Radicals; D000096:Acetone; C026971:coproporphyrin III; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003849:Deoxyguanosine